Features of aggressive tumors include the ability to promote angiogenesis and evade immune surveillance. Natural killer (NK) cells have classically been associated with immune surveillance of tumors and are thought to destroy tumor cells via cytotoxicity. While tumors are often described as wounds that never heal, similarities between embryo implantation and tumor growth/invasion have long been noted. Large influxes of maternal NK cells into the decidua occurs during normal embryo implantation. Originally assumed to be cytotoxic, recent studies indicate that these decidua-NK (dNK) cells have altered CD phenotypes, lose their cytotoxic capacities, elaborate pro-angiogenic factors (VEGF), and facilitate growth of the implant. Mechanisms driving these changes are not established but elaboration of soluble factors by the decidua are thought to direct the unique phenotypic and functional differentiation of the NK cells at the maternal-fetal interface. We propose that similar trans-differentiation of peripheral NK (pNK) cells occurs in renal cell carcinoma (RCC) which then favors growth and metastasis of the tumor. While recent reports highlight a similar potential for tumor infiltrating macrophages (TAM), phenotypic characterization and the pro-angiogenesis role of NK cells in RCC and other tissue-specific cancers has not been investigated. Completion of these studies will provide seminal data that could paradigm shift the generalized role of NK cells in tumor biology and metastasis and provide evidence for the role of PGE2 and/or TGF-beta signaling pathways in activating the angiogenic program. Our hypothesis is based on the notion that soluble factors produced by tumor cells fuels tumor progression through direct recruitment or trans-differentiation of NK cells with angiogenic properties. Prevention of these processes may be an interesting goal of future tumor therapy. Herein, we describe experiments to phenotypically and functionally characterize RCC tumor-infiltrating NK cells and determine if interfering with PGE2 or TGF-beta signaling may be one way to prevent RCC progression and metastasis.